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Antimicrobial Agents and Chemotherapy Feb 2017The safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents.... (Clinical Trial)
Clinical Trial
The safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study with 10 to 13 patients in each of the four dosage cohorts. Each cohort received daily dosages of 2.5, 5.0, 7.5, or 10 mg of amphotericin B in the form of L-AMB per kg of body weight. Neutropenic patients between the ages of 1 and 17 years were enrolled to receive empirical antifungal therapy or treatment of documented invasive fungal infections. The pharmacokinetic parameters of L-AMB were measured as those of amphotericin B by high-performance liquid chromatography and calculated by noncompartmental methods. There were nine adverse-event-related discontinuations, four of which were related to infusions. Infusion-related side effects occurred for 63 (11%) of 565 infusions, with 5 patients experiencing acute infusion-related reactions (7.5- and 10-mg/kg dosage levels). Serum creatinine levels increased from 0.45 ± 0.04 mg/dl to 0.63 ± 0.06 mg/dl in the overall population (P = 0.003), with significant increases in dosage cohorts receiving 5.0 and 10 mg/kg/day. At the higher dosage level of 10 mg/kg, there was a trend toward greater hypokalemia and vomiting. The area under the concentration-time curve from 0 to 24 h (AUC) values for L-AMB on day 1 increased from 54.7 ± 32.9 to 430 ± 566 μg · h/ml in patients receiving 2.5 and 10.0 mg/kg/day, respectively. These findings demonstrate that L-AMB can be administered to pediatric patients at dosages similar to those for adults and that azotemia may develop, especially in those receiving ≥5.0 mg/kg/day.
Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Creatinine; Female; Humans; Immunocompromised Host; Infusions, Intravenous; Male; Neutropenia; Treatment Outcome; Vomiting
PubMed: 27855062
DOI: 10.1128/AAC.01477-16 -
Journal of the American Veterinary... Apr 2018
Topics: Amphotericin B; Animals; Animals, Newborn; Antifungal Agents; Diagnosis, Differential; Diarrhea; Drug Therapy, Combination; Female; Horse Diseases; Horses; Lung Diseases, Fungal; Minocycline; Paecilomyces
PubMed: 29553898
DOI: 10.2460/javma.252.7.813 -
European Journal of Pharmaceutics and... Feb 2023The incidence and prevalence of invasive fungal infections have increased significantly over the last few years, leading to a global health problem due to the lack of...
The incidence and prevalence of invasive fungal infections have increased significantly over the last few years, leading to a global health problem due to the lack of effective treatments. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action. In this work, AmB and ITR have been formulated within granules to elicit an enhanced pharmacological effect, while enhancing the oral bioavailability of AmB. A Quality by Design (QbD) approach was utilised to prepare fixed-dose combination (FDC) granules consisting of a core containing AmB with functional excipients, such as inulin, microcrystalline cellulose (MCC), chitosan, sodium deoxycholate (NaDC) and Soluplus® and polyvinyl pyrrolidone (PVP), coated with a polymeric layer containing ITR with Soluplus® or a combination of Poloxamer 188 and hydroxypropyl methyl cellulose-acetyl succinate (HPMCAS). A Taguchi design of experiments (DoE) with 7 factors and 2 levels was carried out to understand the key factors impacting on the physicochemical properties of the formulation followed by a Box-Behnken design with 3 factors in 3 levels chosen to optimise the formulation parameters. The core of the FDC granules was obtained by wet granulation and later coated using a fluidized bed. In vitro antifungal efficacy was demonstrated by measuring the inhibition halo against different species of Candida spp., including C. albicans (24.19-30.48 mm), C. parapsilosis (26.38-27.84 mm) and C. krusei (11.48-17.92 mm). AmB release was prolonged from 3 to 24 h when the AmB granules were coated. In vivo in CD-1 male mice studies showed that these granules were more selective towards liver, spleen and lung compared to kidney (up to 5-fold more selective in liver, with an accumulation of 8.07 µg AmB/g liver after twice-daily 5 days administration of granules coated with soluplus-ITR), resulting in an excellent oral administration option in the treatment of invasive mycosis. Nevertheless, some biochemical alterations were found, including a decrease in blood urea nitrogen (∼17 g/dl) and alanine aminotransferase (<30 U/l) and an increase in the levels of bilirubin (∼0.2 mg/dl) and alkaline phosphatase (<80 U/l), which could be indicative of a liver failure. Once-daily regimen for 10 days can be a promising therapy.
Topics: Male; Mice; Animals; Amphotericin B; Antifungal Agents; Itraconazole; Mycoses; Candida albicans
PubMed: 36623752
DOI: 10.1016/j.ejpb.2023.01.003 -
Medical Mycology Feb 2019The recorded history of coccidioidomycosis began in 1892 with the report of the illness of Domingo Escurra by Alejandro Posadas followed by a description of the first... (Review)
Review
The recorded history of coccidioidomycosis began in 1892 with the report of the illness of Domingo Escurra by Alejandro Posadas followed by a description of the first North American cases by Rixford and Gilchrist. Originally considered a protozoan, William Ophüls determined that Coccidioides was a fungus and that the lungs were the apparent initial site of infection. During the 1930s, both Gifford and Dickson determined that a self-limited illness, Valley Fever, was caused by the same fungus that caused the often fatal coccidioidal granuloma. Charles Smith, over a period of approximately 2 decades, comprehensively described the clinical and geographic epidemiology of coccidioidomycosis in California. Demosthenes Pappagianis continued this work after Smith's death. In 1957, one year before Marshall Fiese published his masterful monograph on coccidioidomycosis, the use of the first effective agent for the therapy of coccidioidomycosis, amphotericin B, was reported. This was followed by descriptions of its appropriate clinical use by William Winn and by Hans Einstein, among others. The development of the much less toxic azole antifungal agents greatly simplified therapy in many cases, but much of the management of patients with coccidioidomycosis still relies more on art than science. The search for the "Holy Grail" - a vaccine capable of preventing this disease-continues.
Topics: Amphotericin B; Antifungal Agents; Coccidioides; Coccidioidomycosis; History, 19th Century; History, 20th Century; Humans
PubMed: 30690606
DOI: 10.1093/mmy/myy123 -
PLoS Neglected Tropical Diseases Mar 2021There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of...
BACKGROUND
There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic properties of the anti-leishmanial drugs AmBisome and miltefosine in a preclinical disease model of VL.
METHODOLOGY / PRINCIPAL FINDINGS
BALB/c mice were infected with L. donovani (MHOM/ET/67/HU3) amastigotes. Groups of mice were treated with miltefosine (orally, multi-dose regimen) or AmBisome (intravenously, single dose regimen) or left untreated as control groups. At set time points groups of mice were killed and plasma, livers and spleens harvested. For pharmacodynamics the hepatic parasite burden was determined microscopically from tissue impression smears. For pharmacokinetics drug concentrations were measured in plasma and whole tissue homogenates by LC-MS. Unbound drug concentrations were determined by rapid equilibrium dialysis. Doses exerting maximum anti-leishmanial effects were 40 mg/kg for AmBisome and 150 mg/kg (cumulatively) for miltefosine. AmBisome displayed a wider therapeutic range than miltefosine. Dose fractionation at a total dose of 2.5 mg/kg pointed towards concentration-dependent anti-leishmanial activity of AmBisome, favouring the administration of large doses infrequently. Protein binding was >99% for miltefosine and amphotericin B in plasma and tissue homogenates.
CONCLUSION / SIGNIFICANCE
Using a PK/PD approach we propose optimal dosing strategies for AmBisome. Additionally, we describe pharmacokinetic and pharmacodynamic properties of miltefosine and compare our findings in a preclinical disease model to available knowledge from studies in humans. This approach also presents a strategy for improved use of animal models in the drug development process for VL.
Topics: Amphotericin B; Animals; Antiprotozoal Agents; Drug Therapy, Combination; Homeodomain Proteins; Humans; Leishmaniasis, Visceral; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Parasite Load; Phosphorylcholine; Protein Binding
PubMed: 33651812
DOI: 10.1371/journal.pntd.0009013 -
BMC Infectious Diseases Aug 2023Candida auris is an emerging yeast pathogen that can cause invasive infections, particularly candidemia, in healthcare settings. Candida auris is characterized by...
BACKGROUND
Candida auris is an emerging yeast pathogen that can cause invasive infections, particularly candidemia, in healthcare settings. Candida auris is characterized by resistance to multiple classes of antifungal drugs and high mortality.
OBJECTIVE
To describe the risk factors, clinical characteristics, antifungal susceptibility pattern and outcomes of Candida auris blood stream infection.
METHODS
We conducted a retrospective review of electronic medical records of C. auris fungemia cases in the facilities under Hamad Medical corporation, Qatar from 1/11/2018 to 31/7/2021. Demographic data, risk factors, antibiogram and 30-day outcome are described.
RESULTS
We identified 36 patients with C. auris fungemia. Most of the patients were in intensive care unit following severe COVID-19 pneumonia and had received steroids and broad-spectrum antibiotics. Most cases were central line related. Over 90% of isolates were non-susceptible to fluconazole, while amphotericin B resistance reached 85%. Factors associated with high mortality included initial SOFA score of 9 or above and absence of source control.
CONCLUSION
Our study reveals a concerning 41.6% mortality rate within 30 days of C. auris candidemia. Furthermore, the prevalence of amphotericin B resistance in Qatar exceeds what has been reported in the literature necessitating further exploration. Echinocandins retains nearly 100% susceptibility and should be prioritized as the treatment of choice. These findings emphasize the need for vigilant monitoring and appropriate management strategies to combat C. auris infections and improve patient outcomes.
Topics: Humans; Amphotericin B; Antifungal Agents; Candida auris; Candidemia; COVID-19; Microbial Sensitivity Tests; Qatar
PubMed: 37544995
DOI: 10.1186/s12879-023-08477-5 -
Drug Delivery Dec 2021Cryptococcal meningitis is a fungal infectious disease with a poor prognosis and high mortality. Amphotericin B (AMB) is the first choice for the treatment of... (Comparative Study)
Comparative Study
Cryptococcal meningitis is a fungal infectious disease with a poor prognosis and high mortality. Amphotericin B (AMB) is the first choice for the treatment of cryptococcal meninges. The blood-brain barrier (BBB) is the major barrier for the effective delivery of drugs to the brain. In this study, AMB was incorporated in a thermosensitive gel for intrathecal injection. We first synthesized AMB-loaded thermogel, investigated its in vitro cumulative release, and in vivo neurotoxicity, and therapeutic effect. The thermosensitive gel was comprised of 25 wt% poly (lactic acid-co-glycolic acid)-poly (ethylene glycol)-poly (lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock polymer aqueous solution. The AMB loaded in the thermosensitive gel (AMB in gel) had low viscosity at low temperature and resulted in the formation of a non-flowing gel at 37 °C (physiological temperature). AMB loading in gel sustained its release for 36 days and the cumulative release rate was satisfactory. Compared with the AMB solution, intrathecal administration of AMB in gel could reduce the neurovirulence of AMB and get a better treatment effect. The findings of the current study show that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for the delivery of drugs into the intrathecal.
Topics: Amphotericin B; Animals; Antifungal Agents; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogels; Injections, Spinal; Male; Neurotoxicity Syndromes; Polyethylene Glycols; Polyglactin 910; Rats; Rats, Sprague-Dawley; Temperature; Viscosity
PubMed: 33657949
DOI: 10.1080/10717544.2021.1892242 -
Frontiers in Cellular and Infection... 2022Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include...
Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include liposomal formulation or deoxycholate salt of amphotericin B, which has been associated with various complications and severe side effects. Encouraged from the recent marked antimalarial effects from plant-derived glycosides, in this study, we have exploited a green chemistry-based approach to chemically synthesize a library of diverse glycoside derivatives (Gly1-12) and evaluated their inhibitory efficacy against the AG83 strain of . Among the synthesized glycosides, the inhibitory activity of Glycoside-2 (Gly2) (1.13 µM IC50 value) on promastigote demonstrated maximum cytotoxicity with ~94% promastigote death as compared to amphotericin B that was taken as a positive control. The antiproliferative effect of Gly2 on promastigote encouraged us to analyze the structure-activity relationship of Gly2 with Gp63, a zinc metalloprotease that majorly localizes at the surface of the promastigote and has a role in its development and multiplication. The result demonstrated the exceptional binding affinity of Gly2 toward the catalytic domain of Gp63. These data were thereafter validated through cellular thermal shift assay in a physiologically relevant cellular environment. Mechanistically, reduced multiplication of promastigotes on treatment with Gly2 induces the destabilization of redox homeostasis in promastigotes by enhancing reactive oxygen species (ROS), coupled with depolarization of the mitochondrial membrane. Additionally, Gly2 displayed strong lethal effects on infectivity and multiplication of amastigote inside the macrophage in the amastigote-macrophage infection model as compared to amphotericin B treatment. Gp63 is also known to bestow protection against complement-mediated lysis of parasites. Interestingly, Gly2 treatment enhances the complement-mediated lysis of promastigotes in serum physiological conditions. In addition, Gly2 was found to be equally effective against the clinical promastigote forms of PKDL strain (IC50 value of 1.97 µM); hence, it could target both VL and PKDL simultaneously. Taken together, this study reports the serendipitous discovery of Gly2 with potent antileishmanial activity and proves to be a novel chemotherapeutic prototype against VL and PKDL.
Topics: Amphotericin B; Antiprotozoal Agents; Glycosides; Humans; Leishmania donovani; Leishmaniasis, Visceral; Metalloproteases
PubMed: 35601095
DOI: 10.3389/fcimb.2022.803048 -
Indian Journal of Dermatology,... 2022Background Although topical amphotericin B cream is effective for the treatment of nondermatophyte mold onychomycosis in vitro, studies of its effectiveness and safety... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness and safety of topical amphotericin B in 30% dimethyl sulfoxide cream versus 30% dimethyl sulfoxide cream for nondermatophyte onychomycosis treatment: A pilot study.
Background Although topical amphotericin B cream is effective for the treatment of nondermatophyte mold onychomycosis in vitro, studies of its effectiveness and safety in vivo are limited. Objectives We studied the effectiveness and safety of topical 0.3% amphotericin B in 30% dimethyl sulfoxide cream (amphotericin B cream) in nondermatophyte mold onychomycosis using the vehicle cream 30% dimethyl sulfoxide cream as control. Methods This randomized controlled study was conducted between January 2019 and November 2020. Patients diagnosed with nondermatophyte mold onychomycosis were randomly divided into two groups of ten patients each: one treated with amphotericin B cream and the other with the vehicle cream. Clinical and mycological cure as well as safety were evaluated. Results Ten patients each treated with amphotericin B cream and the vehicle cream were included in the study, but only nine patients in the vehicle cream group were available for follow up. All the 19 evaluable patients had distal lateral subungual onychomycosis and the great toenails were affected in 18 (94.7%) of these. Mycological cure was achieved in 8 (80%) patients treated with amphotericin B cream and in 4 (44.4%) patients using the control (vehicle) cream. Clinical cure was achieved in 7 (70%) patients treated with amphotericin B cream, but only in 2 (22.2%) patients on the control cream. No adverse events were observed. Limitations The small sample size and the fact that PCR fungal identification that provides accurate identification of fungal species was not performed are limitations of our study. Conclusion Topical amphotericin B cream was both very effective and safe in the treatment nondermatophyte mold onychomycosis. The control (vehicle) cream containing 30% dimethyl sulfoxide also demonstrated some antifungal activity.
Topics: Administration, Topical; Amphotericin B; Antifungal Agents; Dimethyl Sulfoxide; Foot Dermatoses; Humans; Onychomycosis; Pilot Projects; Treatment Outcome
PubMed: 34877858
DOI: 10.25259/IJDVL_359_2021 -
Parasitology Apr 2018For decades antimonials were the drugs of choice for the treatment of visceral leishmaniasis (VL), but the recent emergence of resistance has made them redundant as... (Review)
Review
For decades antimonials were the drugs of choice for the treatment of visceral leishmaniasis (VL), but the recent emergence of resistance has made them redundant as first-line therapy in the endemic VL region in the Indian subcontinent. The application of other drugs has been limited due to adverse effects, perceived high cost, need for parenteral administration and increasing rate of treatment failures. Liposomal amphotericin B (AmB) and miltefosine (MIL) have been positioned as the effective first-line treatments; however, the number of monotherapy MIL-failures has increased after a decade of use. Since no validated molecular resistance markers are yet available, monitoring and surveillance of changes in drug sensitivity and resistance still depends on standard phenotypic in vitro promastigote or amastigote susceptibility assays. Clinical isolates displaying defined MIL- or AmB-resistance are still fairly scarce and fundamental and applied research on resistance mechanisms and dynamics remains largely dependent on laboratory-generated drug resistant strains. This review addresses the various challenges associated with drug susceptibility and -resistance monitoring in VL, with particular emphasis on the choice of strains, susceptibility model selection and standardization of procedures with specific read-out parameters and well-defined threshold criteria. The latter are essential to support surveillance systems and safeguard the limited number of currently available antileishmanial drugs.
Topics: Amphotericin B; Animals; Antiprotozoal Agents; Drug Resistance, Multiple; Humans; Leishmania donovani; Leishmaniasis, Visceral; Meglumine Antimoniate; Parasitic Sensitivity Tests; Phosphorylcholine; Psychodidae; Recurrence
PubMed: 27866478
DOI: 10.1017/S0031182016002031